Endocrine Emergencies

1
Endocrine Emergencies
2
Adrenal Insufficiency
3
Adrenal physiology

• Cortisol functions at target tissues to maintain
  vascular resistance, cardiac output, hepatic
  glucose production and free water excretion
• Cortisol concentration normally demonstrates
  diurnal variation and increases during times of
  medical stress

4
Adrenal physiology

• The hypothalamus secretes CRH which in turn
  stimulates ACTH production from the pituitary
• ACTH stimlates cortisol production from the
  adrenal glands
• The hypothalamus and pituitary are influenced by
  negative feedback from cortisol

5
Adrenal physiology

• Aldosterone is controlled primarily by
  angiotensin II and circulating potassium levels
  ACTH stimulates aldosterone secretion only
  transiently
• Aldosterone stimulates sodium exchange for
  potassium in the distal nephron

6
Autoimmune Adrenal Insufficiency

• The most common cause of adrenal insufficiency in
  industrialized countries
• May occur alone or associated with other
  autoimmune disorders
• Schmidts syndrome or type II autoimmune
  polyglandular syndrome. Type I diabetes and
  autoimmune thyroid disease
• Type I autoimmune polyglandular syndrome or
  APECED (autoimmune polyendocrinopathy-candidiasis-
  ectomdermal dystrophy) with chronic mucocutaneous
  candidiasis and hypoparathyroidism.

7
Adrenal Hemorrhage

• Increasingly recognized as a cause of adrenal
  insufficiency
• Meningococcemia (Waterhouse-Friderichsen
  syndrome) and other forms of sepsis
• Anticoagulation therapy and coagulation disorders
  including antiphospholipid antibody syndrome
• Severe illness and stress ACTH-induced increases
  in adrenal blood flow that exceeds the capacity
  for venous drainage

8
Infections

• Tuberculosis
• Histoplasmosis
• Cryptococcus
• Blastomycosis
• Paracocciciomycosis
• Cytomegalovirus associated with HIV

9
Adrenoleukodystrophy and Adrenomyeloneuropathy

• X-linked peroxisomal disorders of imparied very
  long chain fatty acid oxidation
• In adrenoleukodystropy the neurological features
  begin in childhood and progress to coma and death
• Adrenomyeloneuropathy neurological features
  (central demyelination, cortical blindness,
  neuropathies) begin in adolescence or young
  adulthood, progress more slowly and involve
  peripheral nerves
• Diagnosis made by measuring high concentrations
  of VLCFA
• Young men with adrenal insufficiency should be
  screened for this disorder

10
Congenital Adrenal Hyperplasia

• A family of autosomal recessive disorders caused
  by deficiency of one of the multiple enzymes in
  the cortisol synthesis pathway
• The enzyme deficiency causes inadequate cortisol
  production and a compensatory increase in ACTH
• ACTH stimulates adrenal hyperplasia and increased
  production of precursors proximal to the block in
  cortisol synthesis

11
Bilateral Adrenal Metastases

• Metastases to the adrenal are common
• Breast 54
• Bronchogenic 44
• Renal 31
• Adrenal insufficiency from metastases is very rare

12
Medications

• Accelerate metabolism of cortisol
• Thyroid hormone
• Rifampin
• Phenytoin
• Phenobarbital
• Mitotane

• Inhibit cortisol synthesis
• Ketoconazole (but not fluconazole or
  itraconazole)
• Etomidate
• Metyrapone
• Mitotane
• Aminoglutethimide

13
Secondary Adrenal Insufficiency

• Pituitary tumors due to mass or treatment of
  tumor
• Metastases to pituitary
• Craniopharyngioma
• Meningioma
• Infiltrative disorders (histiocytosis X,
  lymphocytic hypophysitis,sarcoidosis,
  hemochromatosis)
• Postpartum pituitary necrosis (Sheehans
  syndrome)
• Iatrogenic from exogenous steroids
• High doses of megestrol acetate

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Clinical Presentation
Finding Primary Secondary
Anorexia and weight loss Yes (100) Yes (100)
Fatigue and weakness Yes (100) Yes (100)
Nausea/diarrhea Yes (50) Yes (50)
Muscle,joint,abdominal pain Yes (10) Yes (10)
Orthostatic hypotension Yes Yes
Hyponatremia Yes (80) Yes (60)
Hyperkalemia Yes (60) No
Hyperpigmentation yes No
Secondary deficiencies of testosterone, GH, thyroid, ADH No Yes
Associated autoimmune diseases Yes No
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Adrenal Crisis

• Dehydration, hypotenstion, shock out of
  proportion to severity of current illness,
  nausea, vomiting with anorexia, weight loss,
  unexplained fever, hyponatremia, hyperkalemia,
  azotemia, hypercalcemia, eosinophilia, and
  hypoglycemia
• Often precipitated by intercurrent illness in
  patient with unrecognized adrenal insufficiency
  or in a patient with known disease who did not
  increase cortisol replacement appropriately or
  patient who recently had glucocorticoid therapy
  withdrawn, or in patient with bilateral adrenal
  hemorrhage

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Laboratory Testing

• In acute emergencies treat first, test later
• In the acutely ill patient draw serum cortisol
  and ACTH then treat with dexamethasone 2-4 mg IV
  q12 hours or hydrocortisone 100 mg q6 hours then
  switch to dexamethasone for testing

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Laboratory Testing

• Static testing not very useful
• If cortisol between 8-9 am if less than or equal
  to 3 ug/dl adrenal insufficiency likely
• If cortisol greater than 19 adrenal insufficiency
  ruled out

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Dynamic Testing Cortrosyn

• A serum cortisol of 20 ug/dl or more 1 hour
  following 250 ug of cortrosyn IM or IV excludes
  primary adrenal insufficiency
• Some have suggested a value of 18 is an adequate
  respone
• Difference between baseline and stimulated
  cortisol no longer used
• Does not exclude the presence of secondary
  adrenal insufficiency

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Dynamic Testing Cortrosyn

• Low dose cortrosyn 1 ug IV followed by cortisol
  measurement in one half hour.
• There is evidence for and against the utility of
  this test

20
ACTH Measurements

• In untreated primary adrenal insufficiency ACTH
  is greater than 100 pg/ml
• Not useful for judging adequacy of therapy

21
Insulin Tolerance Test

• Performed fasting in morning
• IV administration of 0.1-0.15 units regular
  insulin/kg
• Cortisol gt18 to 20 during hypoglycemia is normal
• Contraindicated in patients with severe illness,
  coronary artery disease, seizures, psychiatric
  disease
• In patients with pituitary disease growth hormone
  is measured simultaneously

22
Metyrapone Test

• Metyrapone activates the HPA axis by blocking
  cortiosl production at the 11-hydroxylase step,
  the last step in cortisol synthesis
• This leads to cortisol deficiency which should
  activate ACTH production and production of
  precursors proximal to the block
• Metyrapone is given at midnight with a light
  snack
• Cortisol and 11-deoxycortisol are measured at 8
  am. The test is considered normal if cortisol is
  less than 5 and 11-deoxycortisol is at least 7
  ung/dl.

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Once the diagnosis is made a search for the
underlying cause is indicated if not immediately
obviousFor primary adrenal insufficiency
adrenal imaging is indicatedFor secondary
disease MRI imaging of pituitary/hypothalamus may
be needed.
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Treatment

• For primary adrenal crisis hydrocortisone 100
  mg q6 hours if diagnosis established or
  dexamethasone 2-4 mg q12 hours if diagnostic
  testing needed
• For secondary adrenal crisis dexamethasone may
  be preferred to avoid fluid retention and
  hypokalemia
• Intravenous saline to support volume and treat
  hyperkalemia
• Specific mineralocorticoid is usually not
  necessary while using high dose hydrocortisone

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Maintenance Therapy

• Hydrocortisone 10-20 mg in am, 5-10 mg in early
  pm
• Prednisone 5 mg in am, 0-2.5 mg in pm
• Florinef 0-0.1 mg per day
• Adequacy of glucocorticoid judged by patient
  well-being, decrease in pigmentation,
  electrolytes, blood pressure
• Adequacy of mineralocorticoid judged by blood
  pressure, edema, potassium and plasma renin
  activity
• All patients with adrenal insufficiency should
  have MedicAlert bracelet or carry documentation
  of this disorder

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Acute Illness Coverage

• Mild to moderate illness double or triple usual
  glucocorticoid dosage
• Severe illness or vomiting dexamethasone or
  solucortef IM self-administered by patient then
  seek prompt medical help
• Moderately stressful procedures such as
  endoscopy hydrocortisone 100 mg one hour before
  procedure
• Major surgery hydrocortisone 100 mg IV before
  induction of anesthesia and repeated q6 hours.
  Dose then tapered depending on patients rate of
  recovery, usually 50 decrease per day until
  maintenance dose achieved

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Thyroid Storm
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Thyroid Storm

• Severe and life-threatening thyrotoxicosis
• Exaggeration of the typical symptoms of
  hyperthyroidism
• Tachycardia with rate oftengt140
• CHF
• Fever
• Change in mental status delirium, psychosis,
  stupor, coma
• Nausea, vomiting, diarrhea, abdominal pain
• Hepatic failure, jaundice, abnormal liver
  function tests

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Precipitants

• Usually precipitated by an acute event in a
  patient with untreated hyperthyroidism
• Thyroid or nonthyroidal surgery
• Trauma
• Infection
• Acute iodine load or radioactive iodine
• Poor compliance with specific therapy
• Low socioeconomic status
• Preoperative preparation of patients undergoing
  thyroidectomy for hyperthyroidism has led to
  dramatic reduction in prevalence of
  surgically-induced thyroid storm

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Treatment

• IV Fluid
• Acetominophen
• Beta blockade to control adrenergic symptoms
• Thionamide - methimazole or PTU
• Iodine solution to block release of thyroid
  hormone
• Iodinated contrast agent to inhibit the
  peripheral conversion of T4 to T3
• Glucocorticoids to reduce T4 to T3 conversion and
  to treat potential coexistent adrenal
  insufficiency

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Beta Blockers

• Use with caution in patients with CHF or other
  contraindication
• Propranolol is frequently selected as it can be
  given intravenously and reduces the conversion of
  T4 to T3
• Esmolol - loading dose of 250-500 ug/kg IV
  followed by infusion of 50-100 ug/kg/min. This
  permits rapid titration of drug and minimizes
  adverse reactions

32
Thionamides

• Block de novo thyroid hormone synthesis within
  1-2 hours of administration but have no effect on
  preformed thyroid hormone stored in the gland
• PTU blocks conversion of T4 to T3 but since other
  drugs given in storm are usually coadministered
  it is okay to use methimazole which has a longer
  duration of action
• High doses needed Methimazole 30 mg q6 or PTU
  200 mg q4 hours
• Both drugs can be suspected in liquid for rectal
  administration

33
Iodine

• Iodine blocks release of T4 and T3 from the gland
• SSKI 5 drops every 6 hours or Lugols solution 10
  drops tid
• Delay administration of at least one hour after
  thionamide administration to prevent iodine being
  used as a substrate for new hormone synthesis
• If iodine allergic, lithium has been used for the
  same purpose

34
Iodinated Radiocontrast Agents

• Iopanoic acid used for oral cholecystography
• Potent inhibitors of T4 to T3 conversion
• Dose 0.5 to 1 gm qd
• Give at least one hour after thionamide to
  prevent iodine from being used as a substrate for
  new hormone synthesis

35
Glucocorticoids

• Reduce T4 to T3 conversion
• May have a direct effect on underlying autoimmune
  process if storm is due to Graves disease
• Use of glucocorticoids has improved outcome in
  one series
• Hydrocortisone 100 mg IV q8 hours

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Myxedema Coma
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Myxedema Coma

• Severe hypothyroidism due to severe long-standing
  untreated hypothyroidism
• Precipitating acute event almost always present
  infection, myocardial infarction, cold exposure,
  sedative drugs
• Older women affected most frequently
• May result from any of the usual causes of
  hypothyroidism
• Important clues in a poorly responsive patient
  include presence of thyroidectomy scar or history
  of radioiodine treatment or known hypothyroidism
• Mortality rate is high 30-40

38
Clinical Presentation

• Hypothermia
• Decreased mental status
• Hypotension
• Bradycardia
• Hyponatremia
• Hypoglycemia
• Hypoventilation

39
Diagnosis

• History, physical exam, and exclusion of other
  causes of coma
• Treat before waiting for lab confirmation but
  draw TSH, free T4, cortisol before treatment
• Most patients will have primary hypothyroidism
  with high TSH and low free T4 rare patients have
  low free T4 and low TSH consistent with secondary
  hypothyroidism due to hypothalamic or pituitary
  disease
• Cortisol measurement will help exclude coexistent
  adrenal insufficiency

40
Treatment Thyroid Hormone

• Optimal mode of thyroid hormone therapy is
  controversial
• Increasing serum thyroid hormones rapidly carries
  some risk of precipitating MI or atrial
  arrhythmia but this risk must be accepted given
  high mortality rate of myxedema coma
• Levothyroxine 0.2-0.4 mg IV initial dose
• .05 to 0.1 mg IV qd thereafter
• Switch to oral when feasible
• T3 can be given 5-20 ug initially, then 2.5-10 ug
  q8 hours
• Stop T3 when clinical improvement occurs

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Supportive Measures

• Avoid dilute fluids
• Severe hypotension that does not respond to
  fluids should be treated with vasopressors until
  T4 has had time to act
• Passive rewarming with heating blanket (active
  rewarming carries risk of vasodilatation)
• Empiric antibiotics until appropriate cultures
  are proven negative

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Pheochromocytoma
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Catecholamine -Secreting Tumors
Pheochromocytoma and Paragangliomas

• Arise from chromaffin cells of adrenal medulla
  and sympathetic ganglia
• Rare incidence 2-8 cases per million
  prevalence estimates 0.01 to 0.1 of
  hypertensive population
• Occurs equally in men and women, primarily in 3rd
  through 5th decades
• Curable with surgical removal of tumor
• Potential for lethal paroxysm

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Symptoms

• Usually present and are due to pharmacologic
  effects of excess circulating catecholamines
• The five Ps
• Pressure- sudden major increase in BP
• Pain- abrupt onset of throbbing headache, chest
  and/or abdominal pain
• Perspiration- profuse generalized diaphoresis
• Palpitations
• Pallor

45
Spells

• Extremely variable in presentation
• Spontaneous
• Precipitated by diagnostic procedures, postural
  changes, anxiety, exercise, or maneuvers that
  increase intra-abdominal pressure
• Duration 10-60 minutes and may occur daily to
  monthly
• Additional symptoms constipation, attacks of
  hypotension and shock, tremor, anxiety,
  epigastric and chest pain

46
Clinical Signs

• Hypertension - paroxysmal in half, may be severe
  and resistant to conventional therapy
• Orthostatic hypotension
• Pallor
• Grade II-IV retinopathy
• Tremor
• Weight loss
• Fever
• Café au lait spots in neurofibromatosis
• Painless hematuria and paroxysmal attacks induced
  by micturition in pheo of bladder
• Hyperglycemia
• Hypercalcemia
• Erythrocytosis

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Rule of 10

• 10 are extradrenal
• 10 occur in children
• 10 are multiple or bilateral
• 10 recur after surgical removal
• 10 are malignant
• 10 are familial

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Differential Diagnosis

• Endocrine
• Thyrotoxicosis
• Menopausal syndrome
• Hypoglycemia
• Mastocytosis
• Cardiac
• Essential hypertension
• Cardiovascular deconditioning
• Paroxysmal arrhythmia
• Withdrawal of adrenergic inhibiting medications
  (clonidine)
• MAO-inhibitor treatment and ingestion of tyramine
  or decongestant
• Angina

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Differential Diagnosis

• Psychoneurologic
• Anxiety and panic attacks
• Hyperventilation
• Migraine headaches
• Amphetamine, phenylpropanolamine, or cocaine use
• Diencephalic epilepsy
• Factitious
• Sympathomimetic ingestion

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Familial Syndromes

• Familial pheochromocytoma
• MENII a
• Pheochromocytoma
• Medullary thyroid carcinoma
• Hyperparathyroidism
• MENII b
• Pheochromocytoma (bilateral in gt70)
• Medullary thyroid carcinoma
• Mucosal neuromas
• Thickened corneal nerves
• Intestinal ganglioneuromatosis
• Marfanoid body habitus

51
Familial Syndromes

• Neurofibromatosis (von Recklinghausens disease)
• 1 develop pheochromocytoma
• Von Hippel-Lindau (retinal angiomatosis and
  cerebellar hemangioblastoma)
• Additional pheochromocytoma-related
  neurocutaneous syndromes
• Ataxia telangiectasia
• Tuberous sclerosis
• Sturge-Weber
• Other known associations without familial basis
• Carneys triad
• Gastric leiomyosarcoma
• Pulmonary chondroma
• Extra-adrenal pheochromocytoma
• Cholelithiasis
• Renal artery stenosis

52
Paragangliomas

• Para-aortic sympathetic chain
• Organs of Zuckerkandl at origin of inferior
  mesenteric artery
• Wall of urinary bladder
• Sympathetic chain in the neck or mediastinum

53
Other Endocrine Manifestations of
Pheochromocytoma

• GHRH- acromegaly
• ACTH/CRH - Cushings syndrome
• VIP- watery diarrhea
• PTH-RP- hypercalcemia

54
Diagnostic Evaluation

• Biochemical documentation should precede any
  imaging studies
• 24 hour urine collection for catecholamines,
  metanephrine and VMA
• 24 hour urine collection should start with the
  onset of a spell in pateints with episodic
  hypertension
• Usually more than 2 fold increase above the upper
  normal limit
• No role for provocative testing with histamine or
  glucagon

55
Medications Interfering with Assessment

• Increase values
• Tricyclic antidepressants
• Labetolol
• Levodopa
• Decongestants
• Amphetamines, busipirone and most psychoactive
  medications
• Sotalol
• Methyldopa
• Ethanol
• Benzodiazepines
• Decrease values
• Metyrosine
• Methylglucamine

56
Plasma Catecholamines

• Plasma catecholamines
• must be obtained from fasting supine patient with
  indwelling catheter in place for 20 minutes
• affected by diuretics, smoking, renal
  insufficiency
• Plasma metanephrines
• Recent report shows accuracy for diagnosis
• Chromogranin A
• Costored and secreted with catecholamines and
  increased in 80-90 of patients with
  catecholamine secreting tumors
• Neuropeptide Y increased in 87
• Measurements of urinary catecholamines and
  metabolites, chromogranin A, plasma norepi and
  dopamine are invalid In advanced renal
  insufficiency. Plasma epi levels more reliable

57
Localization Studies

• 90 of tumors are found in the adrenal and 98
  are in the abdomen
• Pheos have a characteristic T2-weighted
  appearance on MRI
• Common locations of extradrenal paragangliomas
  are superior para-aortic region in 46, inferior
  para-aortic in 29, urinary bladder in 10,
  thorax in 10, head and neck 3, pelvis 2
• If results of imaging studies are negative an
  MIBG scan can be performed. Sensitivity 88,
  specificity 99

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Treatment of Pheochromocytoma

• Surgical resection after careful pre-op alpha and
  beta adrenergic blockade
• Controls blood pressure and prevents
  intraoperative hypertensive crisis
• Alpha blockade started at least 10 days preop to
  allow for contracted blood volume
• Encourage high salt intake during this time

59
Alpha blockade

• Phenoxybenzamine 10 mg bid and increased 10-20 mg
  every 2 days until BP and spells controlled
• Average dosage 0.5-1.0 mg/kg daily
• Orthostatic hypotension increased, tachycardia,
  miosis, nasal congestion, diarrhea, fatigue

60
Beta blockade

• Administer only after alpha inhibition is
  effective because beta blockade alone may result
  in more severe hypertension due to unopposed
  alpha adrenergic stimulation
• Indicated to control tachycardia associated with
  high circulating catecholamines and alpha
  blockade
• Use cautiously and at low dose as chronic
  circulating catecholamines may cause a
  cardiomyopathy and beta blockers can result in
  pulmonary edema
• Labetolol is a combined beta blocker and alpha
  blocker but instances of paradoxic hypertensive
  crisis (due to incomplete alpha blockade) have
  been reported safety as primary agent is
  controversial

61
Catecholamine Synthesis Inhibitor Metyrosine

• Useful in patients with persistent catecholamine
  producing tumors that cannot be treated with
  combined alpha and beta blockade
• Inhibits tyrosine hydroxylase
• Side effects diarrhea, sedation, anxiety,
  nightmares, urolithiasis, galactorrhea,
  extrapyramidal manifestations

62
Acute Hypertensive Crises

• Phentolamine test dose of 1 mg followed by repeat
  5 mg IV boluses
• Response maximal in 2-3 minutes and lasts 10-15
  minutes
• 100mg/500 cc 5 dextrose can be infused IV and
  titrated to BP control

63
Postoperative Course

• Hypotension may occur after surgery treat with
  fluids and colloid
• Less frequent in patients who have had adequate
  alpha blockade preoperatively
• Hypoglycemia
• BP usually normal prior to discharge
• Some patients remain hypertensive for up to 4-8
  weeks
• 2 weeks after surgery 24 hour urine obtained to
  insure cure then every 5 years